Abstract
Progress in determining the aetiology of schizophrenia (Sz) has arguably been limited by a poorly defined phenotype. We sought to delineate empirically derived cognitive subtypes of Sz to investigate the association of a genetic variant identified in a recent genome-wide association study with specific phenotypic characteristics of Sz. We applied Grade of Membership (GoM) analyses to 617 patients meeting ICD-10 criteria for Sz (n=526) or schizoaffective disorder (n=91), using cognitive performance indicators collected within the Australian Schizophrenia Research Bank. Cognitive variables included subscales from the Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test and the Letter Number Sequencing Test, and standardised estimates of premorbid and current intelligence quotient. The most parsimonious GoM solution yielded two subtypes of clinical cases reflecting those with cognitive deficits (CDs; N=294), comprising 47.6% of the sample who were impaired across all cognitive measures, and a cognitively spared group (CS; N=323) made up of the remaining 52.4% who performed relatively well on all cognitive tests. The CD subgroup were more likely to be unemployed, had an earlier illness onset, and greater severity of functional disability and negative symptoms than the CS group. Risk alleles on the MIR137 single-nucleotide polymorphism (SNP) predicted membership of CD subtype only in combination with higher severity of negative symptoms. These findings provide the first evidence for association of the MIR137 SNP with a specific Sz phenotype characterised by severe CDs and negative symptoms, consistent with the emerging role of microRNAs in the regulation of proteins responsible for neural development and function.
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References
Owen MJ, Craddock N, Jablensky A . The genetic deconstruction of psychosis. Schizophr Bull 2007; 33: 905–911.
O’Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008; 40: 1053–1055.
Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D et al. Common variants conferring risk of schizophrenia. Nature 2009; 460: 744–747.
Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 2009; 460: 753–757.
Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011; 43: 969–976.
Sullivan PF, Lin D, Tzeng JY, van den Oord E, Perkins D, Stroup TS et al. Genomewide association for schizophrenia in the CATIE study: results of stage 1 [published erratum appears in Mol Psychiatry 2009; 14:1144]. Mol Psychiatry 2008; 13: 570–584.
Moskvina V, Craddock N, Holmans P, Nikolov I, Pahwa JS, Green E et al. Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk. Mol Psychiatry 2009; 14: 252–260.
Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–752.
Potash JB . Carving chaos: genetics and the classification of mood and psychotic syndromes. Harv Rev Psychiatry 2006; 14: 47–63.
Jablensky A . Subtyping schizophrenia: implications for genetic research. Mol Psychiatry 2006; 11: 815–836.
Woodbury MA, Clive J, Garson Jr A . Mathematical typology: a grade of membership technique for obtaining disease definition. Comput Biomed Res 1978; 11: 277–298.
Loughland C, Draganic D, McCabe K, Richards J, Nasir A, Allen J et al. Australian Schizophrenia Research Bank: a database of comprehensive clinical, endophenotypic, and genetic data for aetiological studies of schizophrenia. Aust N Z Psychiatry 2011; 44: 1029–1035.
Hallmayer JF, Kalaydjieva L, Badcock J, Dragovic M, Howell S, Michie PT et al. Genetic evidence for a distinct subtype of schizophrenia characterized by pervasive cognitive deficit. Am J Hum Genet 2005; 77: 468–476.
Morar B, Dragovic M, Waters FAV, Chandler D, Kalaydjieva L, Jablensky A . Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition. Mol Psychiatry 2010; 16: 860–866.
Kendler KS, Zachar P, Craver C . Whate kinds of things are psychiatric disorders? Psychol Med 2011; 41: 1143–1150.
John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS . Human microRNA targets. PLoS Biol 2004; 2: e363.
Potkin SG, Macciardi F, Guffanti G, Fallon JH, Wang Q, Turner JA et al. Identifying gene regulatory networks in schizophrenia. Neuroimage 2010; 53: 839–847.
McGuffin P, Farmer A . A polydiagnostic application of operational criteria in studies of psychotic illness: development and validation of the OPCRIT system. Arch Gen Psychiatry 1991; 48: 764–770.
Castle DJ, Jablensky A, McGrath JJ, Carr V, Morgan V, Waterreus A et al. The diagnostic interview for psychoses (DIP): development, reliability and applications. Psychol Med 2006; 36: 69–80.
Buchanan RW, Heinrichs DW . The Neurological Evaluation Scale (NES): a structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry Res 1989; 27: 335–350.
American Psychological Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association: Washington, DC, USA, 1994.
Wechsler D . Wechsler Test of Adult Reading (WTAR). The Psychological Corporation: New York, 2001.
Wechsler D . Wechsler Abbreviated Scale of Intelligence (WASI). The Psychological Corporation: New York, 1999.
Randolph C . Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The Psychological Corporation: San Antonio, TX, 1998.
Wechsler D . Wechsler Adult Intelligence Scales, 3rd edn. The Psychological Corporation: New York, 1997.
Spreen O, Strauss E . A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary. Oxford University Press: New York, 1998.
Jablensky A, Woodbury MA . Dementia praecox and manic-depressive insanity in 1908: a Grade of Membership analysis of the Kraepelinian dichotomy. Eur Arch Psychiatry Clin Neurosci 1995; 245: 202–209.
Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA et al. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol 2007; 8: R27.
Beveridge NJ, Tooney PA, Carroll AP, Gardiner E, Bowden N, Scott RJ et al. Dysregulation of miRNA 181b in the temporal cortex in schizophrenia. Hum Mol Genet 2008; 17: 1156–1168.
Beveridge NJ, Gardiner E, Carroll AP, Tooney PA, Cairns MJ . Schizophrenia is associated with an increase in cortical microRNA biogenesis. Molecular Psychiatry 2010; 15: 1176–1189.
Santarelli DM, Beveridge NJ, Tooney PA, Cairns MJ . Upregulation of dicer and microRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia. Biol Psychiatry 2011; 69: 180–187.
Gardiner E, Beveridge NJ, Wu JQ, Carr V, Scott RJ, Tooney PA et al. Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells. Mol Psychiatry advance online publication, 5 July 2011; e-pub ahead of print (doi: 10.1038/mp.2011.78).
Schratt G . Fine-tuning neural gene expression with microRNAs. Curr Opin Neurobiol 2009; 19: 213–219.
Smrt RD, Szulwach KE, Pfeiffer RL, Li X, Guo W, Pathania M et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 2010; 28: 1060–1070.
Willemsen MH, Valles A, Kirkels LAMH, Mastebroek M, Olde Loohuis N, Kos A et al. Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability. J Med Genet 2011; 48: 810–818.
Green MJ, Matheson SL, Shepherd A, Weickert CS, Carr VJ . Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry 2011; 16: 960–972.
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M et al. A brain-specific microRNA regulates dendritic spine development [published erratum appears in Nature 2006; 441:902]. Nature 2006; 439: 283–289.
Beveridge NJ, Tooney PA, Carroll AP, Tran N, Cairns MJ . Down-regulation of miR-17 family expression in response to retinoic acid induced neuronal differentiation. Cell Signal 2009; 21: 1837–1845.
Bilder RM, Volavka J, Czobor P, Malhotra AK, Kennedy JL, Ni X et al. Neurocognitive correlates of the COMT Val(158)Met polymorphism in chronic schizophrenia. Biol Psychiatry 2002; 52: 701–707.
Wang Y, Fang Y, Shen Y, Xu Q . Analysis of association between the catechol-O-methyltransferase (COMT) gene and negative symptoms in chronic schizophrenia. Psychiatry Res 2010; 179: 147–150.
Acknowledgements
This research was supported by the Australian National Health and Medical Research Council (NHMRC) Project Grant held by Green (No. 630471), using data from the Australian Schizophrenia Research Bank, funded by NHMRC Enabling Grant (No. 386500) held by V Carr, U Schall, R Scott, A Jablensky, B Mowry, P Michie, S Catts, F Henskens and C Pantelis (Chief Investigators), and the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, as well the Schizophrenia Research Institute, using an infrastructure grant from the NSW Ministry of Health. MJG was supported by an Australian Research Council Future Fellowship (FT0991511). We acknowledge Carmel Loughland, Kathryn McCabe and Jason Bridge for the management and quality control of data obtained from the Australian Schizophrenia Research Bank.
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Green, M., Cairns, M., Wu, J. et al. Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia. Mol Psychiatry 18, 774–780 (2013). https://doi.org/10.1038/mp.2012.84
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DOI: https://doi.org/10.1038/mp.2012.84
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